Systems and methods for atraumatic implantation of bio-active agents

ABSTRACT

Methods and apparatus are provided for delivering a bioactive agent in a needle track formed in a target tissue mass, following formation of the needle track, by avoiding impingement of the agent against target tissue at high velocity or by using capillary action to draw the bioactive agent out of the needle during needle withdrawal. The apparatus comprises a catheter and a needle disposed within the catheter and configured to be selectively extended into the tissue mass to a predetermined depth, while dispensing the agent simultaneously with retraction of the needle along the needle track. Alternatively, or in addition, the needle may be configured to create a tissue space surrounding a distal or lateral surface of the needle, into which the bioactive agent to be infused.

FIELD OF THE INVENTION

The present invention relates to delivery systems and methods fordelivering fragile bio-active agents, such as stem cells or myoblasts,into a target tissue using a passive or controlled injection deploymenttechniques that reduces trauma to the bio-active agent and/or collateraldamage to the host tissue.

BACKGROUND OF THE INVENTION

Cardiovascular disease is the leading cause of death in the industrialworld today. During the disease process, atherosclerotic plaques developat various locations within the arterial system and restrict the flow ofblood through the affected vessels. When such plaque develops within theblood vessels that feed the muscles and other tissues of the heart,myocardial infarctions and ischemia due to reduced blood flow to theheart tissues may result.

Over the past decades numerous devices and methods have been evaluatedfor preventing myocardial ischemia or cell death, including but notlimited to: traditional surgical methods (e.g. open heart surgery),minimally invasive surgery, interventional cardiology (e.g. angioplasty,atherectomy, stents), and catheter based delivery of bioactive agents,including growth factors, genes and stem cells.

Open surgical methods for treating cardiovascular disease typicallyinvolve surgically accessing the heart to bypass blockages in thecoronary blood vessels. Based upon the degree of coronary arterydisease, a single, double, triple, or even greater number of vessels arebypassed by creating a conduit from the aorta or pedicle internalmammary artery to a stenosed coronary artery, at a location distal tothe occluded site, using either synthetic or natural bypass grafts. Suchprocedures generally involve significant pain, extended rehabilitationtime and high morbidity, and are time-consuming and costly to perform.

Minimally invasive surgical approaches have been developed whereinlimited access is obtained to the heart and affected vessels using smallincisions made through the ribs. While these methods reduce pain andrehabilitation time, they are available for a relatively limited numberof procedures.

Interventional cardiology apparatus and methods, such as percutaneoustransluminal coronary angioplasty (PTCA), rotational atherectomy, andstenting, have been developed to overcome some of the drawbacks of openand minimally-invasive surgical methods. While many patients aresuccessfully relieved of symptoms with interventional procedures, asignificant number of patients still experience irreversible myocardialinjury related to abrupt closure or restenosis of the blood vesselswithin a relatively short period of time after the interventionalprocedure.

Work is currently in progress to develop advanced apparatus and methods,such as drug-coated stents, to delay or prevent restenosis. In addition,as described in Local Drug Delivery for the Treatment of Thrombus andRestenosis, IAGS Proceedings, J. Invasive Card., 8:399-408, October1996, some practitioners augment standard catheter-based treatmenttechniques with devices that provide local delivery of medications tothe treated site, with the goal of counteracting clotting, reducinginflammatory response, and blocking proliferative responses.

All of the foregoing methods are primarily intended to restore patencyof a stenosed vessel thus improve blood flow to tissues downstream butcannot cause the muscle in the infarcted zones to regenerate.Transmyocardial revascularization was conceived as a method ofsupplementing the blood supply delivered to the heart by creatingchannels, either mechanically or by laser ablation, that extend from theendocardial surface of the left ventricle into the myocardial muscle. Itwas believed that such techniques could engender an angiogenic response,in which new blood vessels would form in the vicinity of the ventricularchannels. The reported results for such techniques were disappointing,and such approaches have essentially been abandoned.

More recent efforts for regenerating healthy tissue in affected areas ofthe heart muscle involve percutaneous or direct injection of bioactiveagents to the affected tissue areas, including gene vectors, growthfactors, myoblasts and stem cells. For example, Mack et al., in anarticle entitled Biologic Bypass with the Use of Adenovirus-MedicatedGene Transfer of the Complementary Deoxyribonucleic Acid for VascularEndothelial Growth Factor 121 Improves Myocardial Perfusion and Functionin the Ischemic Porcine Heart, J. Thor. & Card. Surg. 115:168-177(January 1998) describes experiments to improve myocardial perfusionusing growth factors. Sanborn et al., Percutaneous Endocardial GeneTherapy: In Vivo Gene Transfer and Expression, J. Am. Coll. Card.33:262A (February 1999) describe the injection of angiogenic proteinsand genes directly into the heart via the endocardium using apercutaneous fluoroscopically guided system. Uchida et al., AngiogenicTherapy of Acute Myocardial Infarction by Intrapericardial Injection ofBasic Fibroblast Growth Factor and Heparin Sulfate: An ExperimentalStudy, Am. Heart J. 130:1182-1188 (December 1995), describe growthfactor injections into the pericardial cavity using a catheter systeminserted through the right atrium. U.S. Pat. No. 5,244,460 to Unger etal. describes a method for infusing bioactive agents containing bloodvessel growth promoting peptides (i.e. fibroblast growth factor) via acatheter inserted into a coronary artery.

Thompson et al., in Percutaneous Transvenous Cellular Cardiomyoplasty,J. Am. Coll. Card., 41(11):1964-1971 (June 2003), describe apparatus andmethods for pressurized injection of cultured autologous bone marrowcells, suspended in a biodegradable biogel polymer, into the myocardiumusing percutaneous access via the coronary sinus. An ultrasound-guidedcatheter was used to place a needle into a coronary vein, the needle wasthen extended into the myocardium, and a floppy catheter disposed withinthe needle was advanced into the myocardium to deliver the bone marrowcells. The article describes that the biodegradable polymer is used toreduce physical compression and lysis of the cells as they are injectedinto the target tissue.

U.S. patent application Publication No. US 2003/0191449 to Nash et al.describes a system for pressurized endocardial injection of bioactivematerials, including growth factors, stem cells, etc., into themyocardial tissue using an endocardial approach. U.S. Pat. No. 6,432,119to Saadat describes methods and apparatus for endocardial delivery ofautologous angiogenic substances to myocardium in connection withmechanical percutaneous transmyocardial revascularization. U.S. Pat. No.6,120,520 to Saadat et al. describes a system for providing endocardialinjection of bioactive agents from a pressurized source.

As noted in the foregoing Thompson article, needle withdrawal in thepreceding systems may provide an exit point for cells or gene therapysubstrates to be released into systemic circulation, with a concomitantrisk of embolization. In addition, pressurized injection of certainbioactive agents, such as stem cells, is expected to inflict physicaldamage to the cell membranes due to fluid turbulence and pressurefluctuations encountered during the injection process (referred toherein as “barotrauma”), resulting in lysis of the cells that maysignificantly reduce the yield of viable cells delivered at theinjection site and/or trauma to the target tissue.

Further, depending upon the degree of pressure-regulation of theinjection system, it may in addition be possible for some of theinjected bioactive agent to be expelled from the needle track during theinjection process, e.g., due to systolic muscle contraction. Forcefulinjection of any material into tissue also may disrupt the delicateintercellular matrix, thereby causing target tissue cellular injury.Also, if a needle were to be inadvertently inserted into a smallmyocardial vessel, forceful injection may result in shear stress injuryto the vessel or embolization to the pulmonary artery or remote tissue.

In view of these drawbacks of previously known devices, it would bedesirable to provide methods and apparatus for delivering bioactiveagents, especially fragile bioactive agents, in such a way that reducesthe risk of inflicting barotrauma on the bioactive agent and targettissue during delivery while at the same time minimizing the risk ofembolization

It further would be desirable to provide methods and apparatus fordelivering bioactive agents, especially fragile bioactive agents, thatreduces the need for biodegradable carriers, such as biogels, to cushiondelivery of the bioactive agents, thus reducing the risk of embolizationresulting from release of such material into systemic circulation whilealso preserving the integrity of the target tissue.

It further would be desirable to provide methods and apparatus fordelivering cells to damaged tissue to promote tissue regeneration,wherein the delivery systems and methods reduce physical trauma to thecell membranes during delivery, and enhance the proportion of viablecells delivered to the damaged tissue.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide methods and apparatus for delivering bioactive agents thatreduces the risk of inflicting barotrauma on the bioactive agent ortarget tissue during delivery.

It is another object of this invention to provide methods and apparatusfor delivering bioactive agents, especially fragile bioactive agents,that reduces the need for biodegradable carriers, such as biogels, tocushion delivery of the bioactive agents, thus reducing the risk ofembolization resulting from release of such material into systemiccirculation.

It is a further object of the present invention to provide methods andapparatus for delivering cells to damaged tissue to promote tissueregeneration, wherein the delivery systems and methods reduce physicaltrauma to the cell membranes during delivery, and enhance the proportionof viable cells delivered to the damaged tissue.

These and other objects of the present invention are accomplished byproviding methods and apparatus for delivering bioactive agents,especially fragile bioactive agents, wherein the bioactive agent isatraumatically deployed in a needle track formed in a target tissue massfollowing formation of the needle track. In the context of the presentinvention, “atraumatic” deployment means deployment of the bioactiveagent without generating turbulent fluid motion that inflicts physicaldamage to the bioactive agent, e.g., due to high shearing stresses orpressure fluctuations.

In accordance with the principles of the present invention, deploymentof bioactive agents is accomplished using needle arrangements that avoidimpingement of the bioactive agent against target tissue at highvelocity or employ capillary action to draw the bioactive agent out ofthe needle during needle withdrawal. Alternatively, the presentinvention could hold the column of biologic material stationaryutilizing a proximal syringe or internal piston while the needle isbeing retracted. While the present invention is described in the contextof promoting regeneration of myocardial tissue, the apparatus andmethods of the present invention may be advantageously employed whereverit is desired to promote tissue regeneration.

In accordance with a first aspect of the present invention, apparatus isprovided for delivering a bioactive agent, such as a suspension of stemcells, into the myocardium through the endocardial surface. Theapparatus preferably comprises a catheter that may be deployed in theleft ventricle, and a needle disposed from the catheter and configuredto be selectively extended into the myocardium through the endocardialsurface to a predetermined maximum depth.

In a first embodiment, the apparatus further comprises a delivery systemthat applies and dispenses the bioactive agent while simultaneouslyretracting the needle from a maximum predetermined depth, so that thestem cell suspension is deployed along the needle track. In a preferredembodiment, the delivery system provides no positive pressure to injectthe bioactive agent, but merely enables the bioactive agent to be drawnout of the distal tip of the needle, during needle retraction, bycapillary action. Alternatively, the needle may be advanced having acolumn of fluid disposed within it, and the column of fluid may then beheld stationary while the needle is retracted.

In an alternative embodiment, the needle further comprises means forcreating a tissue space surrounding a distal or lateral surface of theneedle, thereby permitting bioactive agent to be infused into the spacewithout retracting the needle. The means for creating the tissue spacemay take the form of one or more expandable struts that are deployed tocreate a space surrounding the needle, and permit the bioactive agent tobe infused into apertures that rest in a lateral surface of the needle.Alternatively, the needle may be fluted or grooved, so that the outeredges of the flutes support the tissue and form a space into which thebioactive agent may be infused via apertures at the base of the flutes.

The catheter system of the present invention further may include astructure for positioning and stabilizing the needle against theendocardial surface during infusion of the bioactive agents. Thisstructure may comprise one or more guide rails that transition from acontracted delivery configuration to a deployed configuration in theventricular chamber, such have been developed for transmyocardialrevascularization. Alternatively, the positioning and stabilizingstructure may comprise a relatively flexible catheter and a plurality ofpre-formed stylets that are configured to be selectively inserted intothe flexible catheter to conform the catheter to specific regions of thecardiac chambers. Thus, the present invention provides means (e.g., oneor more guide rails or pre-formed stylets) for stabilizing the catheterand needle within a hollow organ, such as a cardiac chamber.

In accordance with another aspect of the present invention, apparatus isprovided for delivering a bioactive agent, such as a suspension of stemcells, into the myocardium through the epicardial surface via accessfrom the cardiac veins. In this embodiment the apparatus preferablycomprises a catheter that may be deployed via deep vein through theinferior or superior vena cava into the coronary sinus, great cardiacvein and adjoining vessels. A needle disposed from a distal or lateralsurface of the catheter is configured to be selectively extended intothe myocardium through the epicardial surface to a predetermined depth.Infusion of bioactive agents into the myocardium may be accomplishedeither by depositing the agent into the needle track while withdrawingthe needle (or holding the column of fluid stationary while retractingthe needle) or by creating a tissue space surrounding the needle asdescribed for the endocardial access embodiment.

The needle exit port of the catheter may be directed towards themyocardium using a positioning balloon disposed on the opposite side ofthe catheter from the exit port, so that when the balloon is inflated itpreferentially turns the device inward. Similarly the exit port could bedirected inward using fluoroscopy, electrical mapping or intravascularultrasound.

Methods of using the catheters of the present invention, for example, topromote regeneration of cardiac and other tissues also are provided.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description of the preferred embodiments, in which:

FIGS. 1A-1C are views depicting previously known methods of injectingdrugs and other bioactive agents into a tissue mass;

FIGS. 2A-2C are views depicting a method of injecting drugs and otherbioactive agents into a tissue mass in accordance with the principles ofthe present invention;

FIGS. 3A and 3B are views depicting an alternative method of the presentinvention for injecting drugs and other bioactive agents into a tissuemass;

FIGS. 4A and 4B depict, respectively, a side view of apparatus of thepresent invention and a detailed view of the handle portion;

FIG. 5 depicts a detailed view of an alternative handle portion suitablefor use with the apparatus of the present invention;

FIGS. 6A and 6B depict, respectively, a side view of alternativeapparatus of the present invention and a detailed view of the handleportion that device;

FIG. 7A is a side view of an alternative distal tip of a needle suitablefor use in the apparatus of FIGS. 4 and 5;

FIG. 7B is a cross-sectional view of FIG. 7A;

FIGS. 8A and 8B are side views of an alternative distal tip of a needlesuitable for use in the apparatus of FIGS. 4-6;

FIGS. 9A-9C are views of a guide system suitable for use with thecatheters of FIGS. 4-6 for use in delivering bioactive agents to theinterior of a hollow organ;

FIGS. 10A and 10B are, respectively, a side view of the catheter of thepresent invention engaged with an alternative guide system and adetailed view of the distal end of the guide system;

FIGS. 11A-11C show a further alternative rail system for use with thecatheter of the present invention and a method of using same;

FIGS. 12A-12D show a stylet system for use with the catheter of thepresent invention and a method of using same;

FIG. 13 depicts the arrangement of the coronary veins in a human heart;

FIG. 14 shows a distal end of a catheter of the present inventionsuitable for use in delivering bioactive agents to the myocardium viathe coronary veins; and

FIGS. 15A and 15B illustrate a method of using the apparatus of FIG. 14to deliver bioactive agents to the myocardium via the coronary veins.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and apparatus fordelivering bioactive agents, especially fragile bioactive agents, byatraumatically depositing the bioactive agent in a needle track formedin a target tissue mass, following formation of the needle track. In thecontext of the present invention, “atraumatic” deployment refers todeploying the bioactive agent without the generating turbulent fluidmotion that inflicts physical damage to the bioactive agent or targettissue, e.g., due to high shearing stresses or pressure fluctuations(“barotrauma”).

In accordance with the principles of the present invention, deploymentis accomplished using needle arrangements that avoid impingement of thebioactive agent against target tissue at high velocity, or capillaryaction, which draws the bioactive agent out of the needle during needlewithdrawal. Alternatively, a column of bioactive agent disposed withinthe needle may be advanced in unison with the needle, and then heldstationary or a low volume is injected forward while the needle isretracted, thereby during insertion of the needle, controlled by aproximal deploying the bioactive agent without pressurized injection.Alternatively, or in addition, the needle may comprise expandable strutsor grooves for creating a tissue space surrounding a distal or lateralsurface of the needle, thereby permitting bioactive agent to be infusedinto the space without retracting the needle. Thus, the presentinvention provides optional means (e.g., expandable struts or grooves)for creating a space adjacent to the distal end of the needle to receivethe bioactive agent.

Referring to FIGS. 1A-1C, some of the drawbacks of previously knownbioactive agent delivery systems are described. As discussed above, someresearches currently are investigating regeneration of tissue, e.g.,heart tissue, by injecting stem cells into the tissue to promoteangiogenesis or the formation of new heart tissue. FIG. 1A illustratespreviously known injection needle 10 being brought into approximationwith tissue mass T, such as the endocardial surface of the leftventricle.

Once the tip of needle 10 is inserted into the tissue, as shown in FIG.1B, bioactive agent B, such as a drug, is injected into the tissue mass.Applicant has concluded that pressurized injection of the bioactiveagent may have a substantial detrimental effect both on the agentdelivered and the tissue to be treated. With respect to the tissue,applicant has observed that pressurized injection of fluid may cause thetissue to tear along naturally-occurring striations S, thus weakeningthe muscle. In addition, the bioactive agent is expected to pool alongthe membrane surfaces of the striations.

Applicant also has observed that pressurized injection also causesturbulence that causes the injectate stream to impinge violently againstthe tissue as it leaves the tip of the injection needle. In addition,the injectate may experience rapid pressure fluctuations. These effectsmay lyse the bioactive agent, particularly where the agent comprisesstem cells, by rupturing the cell membrane or damaging the cellularcomponents. Applicant therefore has theorized that a much higher yieldof viable cells may be delivered to a target tissue if apparatus andmethods could be provided to avoid stationary pressurized injection.

One approach suggested by researchers in the field of stem cellinjection is to suspend the stem cells in a biocompatible gel to cushionthe cells during injection. As discussed above with respect to theThompson article, this approach presents the potential for the injectateto exit the needle track and embolize. As illustrated in FIG. 1C, onceneedle 10 has been withdrawn from the needle track N, systolic musclecontraction may cause some of the injected bioactive agent B to beexpelled from the needle track. If a biogel were used, this could resultin thrombus formation with potentially dire consequences for thepatient.

Referring now to FIGS. 2A to 2C, apparatus and methods of the presentinvention are described that overcome the drawbacks of previously knownsystems for delivering fragile bioactive agents, such as stem cells. Asshown in FIG. 2A, in accordance with the principles of the presentinvention, needle 20 is first approximated to endocardial tissue mass T.In FIG. 2B, needle 20 is shown inserted into the tissue mass. In FIG.2C, as needle 20 is withdrawn from the tissue mass, bioactive agent B isdrawn out of the tip of the needle and deposited in the needle track.

Because in the present invention the bioactive agent is not injectedunder pressure into the tissue, there will be substantially lessturbulence and pressure fluctuation imposed on the agent as it exitsneedle 20. Also, the bioactive agent will not damage the tissue mass bysplitting the tissue along the naturally-occurring striations, as inFIG. 1B. In addition, because a pool of bioactive agent will notaccumulate along the striations, there is less risk that the bioactiveagent will be expelled from the tissue during cardiac contractions.Also, retraction of the needle will minimize the risk of inadvertentinjection of the full load into a vessel.

FIGS. 3A and 3B illustrate catheter 25 having multiple needles 20 thatcurve away from one another when inserted in tissue mass T. Catheter 25is arranged so that the needles may be simultaneously extended into thetissue mass to form needle tracks, as depicted in FIG. 3A. Needles 20then are retracted, so that bioactive agent B is drawn from the needletips by capillary action. As depicted in FIG. 3B, an arrangement ofmultiple needles will permit a larger area of the tissue mass to receivethe stem cells for a single actuation of catheter 25.

Although three needles 20 are illustrated in FIGS. 3, it will beunderstood that any number of needles may be used in the accordance withthe principles of the present invention. For example, according to someembodiments, a spiral needle is rotated into the muscle mass and rotatedin the opposite direction as the biologic agent is released. Moreparticularly, as the spiral shaped needle is advanced, it will rotate ina first direction and “corkscrew” into the muscle. As the needle isrotated in the opposite direction, the biologic agent is injected as theneedle retracts. Such an injection during retraction mechanismadvantageously can be used to inject the liver or other organ from anendovascular (catheter) approach or a non-catheter transmutationsapproach.

Referring now to FIG. 4A, delivery system 30 of the present invention isdescribed. Delivery system 30 comprises catheter 31, elongated needle 34and handle 35. Catheter 31 preferably includes guide member 32 disposedadjacent to distal tip 33, which permits the distal end of the catheterto be slidably coupled to a guide rail, as described hereinbelow withrespect to FIGS. 8-11.

Elongated needle 34 is slidably disposed within a lumen of catheter 31,and includes handle 35 disposed in proximal region 36 andtissue-piercing tip 37 that may be selectively extended beyond thedistal end of catheter 31. Needle 34 includes an internal lumen thatextends from the proximal end 38 of the needle to tip 37. Proximal end38 is coupled via valve 39 to vial 40 containing a suitable bioactiveagent, such as a suspension of stem cells. Handle 35 includes mechanism41 that reciprocates distal tip 37 of the needle to form a needle track,and facilitates delivery of bioactive agent from vial 40 through a lumenof needle 34 to the targeted tissue.

As shown in FIG. 4B, handle 35 comprises grip 42 carrying pivotallymounted lever 43. Needle 34 is coupled to upper portion 44 of lever 43via pin 45 that is disposed to slide in slot 46 of upper portion 44.Grip 42 includes upper portion 47 that carries piston 48. Rod 49 ofpiston 48 is coupled to block 50 that is fixedly mounted to needle 34.Spring 51 is disposed over needle 34 and is captured between block 50and upper portion 47 of grip 42, and biases rod 49 to its extendedposition.

Valve 39 selectively couples vial 40 to the lumen of needle 43, and isoperated by the clinician during actuation of handle 35 to deploybioactive agent in the needle track formed by the distal tip of theneedle. According to some embodiments, the device is modified such thatvalve 39 automatically releases during needle withdrawal. Vial 40preferably includes one-way valve 52 that permits bioactive agent to bedrawn from the vial during retraction of the needle from the tissuemass.

In operation, handle 35 is held by the clinician so that, after distalregion 33 of catheter 31 is disposed proximate a tissue mass, lever 43may be depressed. This causes the distal tip of the needle to beextended into the tissue mass while simultaneously compressing spring 51and compressing piston 48. The clinician then opens valve 39 to couplethe bioactive agent, e.g., suspension of stem cells, to the lumen ofneedle 34, and releases lever 43. Alternatively, valve 39 may be aone-way valve that permits bioactive agent to flow from vial 40 into theneedle, but prevents reverse flow. In this case, valve 39 would openautomatically during needle retraction, but would remain closed duringneedle insertion.

When the clinician releases lever 43, spring 51 urges block 50 in theproximal direction, thereby retracting distal tip 37 of the needle fromthe needle track. The rate at which the spring returns the upper portion44 of lever 43 to its proximal-most position is determined by piston 48.This return rate preferably is selected to cause a desired amount ofbioactive agent to be deposited in the needle track, without damagingthe tissue or creating the potential for leakage of the bioactive agentinto the left ventricle via the needle track entrance.

Valve 39 and one-way valve 52 are used to control the deposition of thebioactive agent from needle 34 during formation of the needle track andretraction of the needle. In particular, valve 39 is closed duringextension of needle 34, so that the column of bioactive agent in thelumen of the needle is substantially incompressible, and prevents atissue core from entering and occluding the distal tip of the needle.Once lever 43 has been compressed to cause a desired extension theneedle tip into the tissue mass, valve 39 couples the needle lumen tothe contents of vial 40. One-way valve 52 ensures that during retractionof the needle, a negative pressure does not develop within vial 40 thatcould impede having the bioactive agent drawn from the distal tip of theneedle by capillary action.

Before the distal tip of needle 34 retracts from within the needletrack, valve 39 closes to decouple vial 40 from the lumen of needle 34.This prevents the bioactive agent from being deposited at the needletrack entrance, and reduces the risk that the bioactive agent will beejected from the needle track entrance and embolize. Catheter 31 maythen be repositioned, and the above process repeated. Depending upon theselection of valve 39, operation of valve 39 may be controlled by thephysician or may be arranged to operate automatically.

Referring to FIG. 5, an alternative handle portion suitable for use withthe apparatus of the present invention will now be described. Handle 35′comprises grip 42′ carrying pivotally mounted lever 43′. An upperportion 44′ of grip 42′ is attached to a ratchet member 53 via pin 45′,which is disposed to slide within slot 46′ of upper portion 44′. Ratchetmember 53 includes a distal end having a plurality of notches 53 a thatare dimensioned to receive corresponding teeth 54 a projecting from gear54. Gear 54 is selectively coupled to lobed cam 55 so that rotation ofgear 54 in a counterclockwise direction causes cam 55 to rotate in acounterclockwise direction. However, when gear 54 is rotated in aclockwise direction, it does not engage cam 55, but instead spinsfreely.

Needle 34′ preferably includes pin 56 attached thereto such that aquarter turn of cam 55 initially forces the needle distally, and thenpermits the needle to retract proximally to its original position underthe force of spring 51′. As the needle retracts, plunger 56 is urgeddistally by spring-loaded arm 57, which is pivotally attached to aproximal end of ratchet member 53. More particularly, the distalmovement of ratchet member 53 forces spring-loaded arm 57 into contactwith projection 56 a on plunger 56, thereby forcing bioactive agentdisposed within syringe 58 to be forced through the needle lumen andejected from the distal tip only during retraction of the needle fromthe tissue mass. After the clinician releases the lever, spring 59returns the lever to its original position and ratchet member 53 isurged proximally back to its original position. Since gear 54 does notengage cam 55 during clockwise rotation, needle 34′ does not move aslever 43′ is returned.

In operation, the distal region of the delivery catheter is disposedproximate a target tissue. Handle 35′ is held by the clinician and lever43′ is depressed, thereby causing the ratchet member to move proximally.Proximal movement of ratchet member 53 rotates the gear and cam 55, thuscausing the distal tip of the needle to be extended into the tissuemass. However, the bioactive agent is not injected into the tissue massat this time due to a predetermined amount of spacing betweenspring-loaded arm 57 and plunger projection 56 a. As the clinicianfurther depresses the lever, the needle is retracted (due to the lobedshape of cam 55), and continued distal movement of the ratchet membercauses spring-loaded arm 57 to contact projection 56 a and depress theplunger. Thus, the bioactive agent is injected during needle retractionrather than during needle insertion.

Referring to FIGS. 6A and 6B, an alternative embodiment of a deliverysystem constructed in accordance with the principles of the presentinvention is described. Delivery system 60 comprises catheter 61,elongated needle 62, handle 63 and syringe 64. As for the previousembodiment, catheter 61 preferably comprises guide member 65 disposedadjacent to distal tip 66, so that catheter 61 may be slidably coupledto a guide rail, as described hereinbelow with respect to FIGS. 8-11.

Elongate needle 62 is slidably disposed within a lumen of catheter 61,and is coupled to handle 63 disposed in proximal region 67 andtissue-piercing tip 68 that may be selectively extended beyond thedistal tip 66 catheter 61. Needle 62 includes an internal lumen thatextends from its proximal end to tip 68. The proximal end of needle 62is coupled via fitting 69 to syringe 64. Syringe 64 contains a suitablebioactive agent, such as a suspension of stem cells. Handle 63 isconfigured to selectively extend and retract tip 68 of the needle toform a needle track.

With respect to FIG. 6B, handle 63 comprises body portion 70 coupled toactuator 71 via threaded portion 72. Needle 62 is affixed only toactuator 71 at base 73, and freely translates through body portion 70when the actuator 71 is rotated on threaded portion 72. In this manner,needle 62 may be reciprocated through a predetermined distance byrotating actuator 71 relative to body portion 70, thereby extending andretracting tip 68 of needle 62 through that predetermined distance.

Syringe 64, may be conventional in construction and preferably includespiston 74 disposed within the syringe so that forward movement of thepiston ejects the contents of the syringe into the lumen of needle 62.Once tip 68 of needle 62 has been extended into a tissue mass, piston 74of syringe 64 is actuated to dispense bioactive agent from the syringeinto the needle track.

Referring now also to FIGS. 7A and 7B, in accordance with the principlesof the present invention, tip 68 is configured to reduce barotrauma andthe imposition of high shears stresses on the bioactive agent duringdelivery into the needle track. Tip 68 of needle 62 illustrativelyincludes V-shaped grooves 80 that extend inwardly from the surface ofthe needle. As shown in FIG. 7B, apertures 81 are disposed in grooves 80and communicate with lumen 82, which extends back to handle 63 where thelumen communicates with syringe 64 (see FIG. 6B). When extended intotissue T, grooves 81 suspend the tissue away from the exterior surfacesof the grooves, to create pockets P into which the bioactive agent maybe deposited. In this manner, the bioactive agent may be deposited inpockets P formed within tissue T using a low pressure injection, and arenot subjected to high shear stresses as the bioactive agent impingesupon the surrounding tissue.

Operation of the apparatus of FIGS. 6 and 7 is as follows. Once theclinician has located tip 66 of catheter 61 proximate to a desiredtissue mass (for example, as with respect to FIGS. 9-12 below), bodyportion 70 of handle 63 is held stationary while actuator portion 71 isrotated on threaded portion 72. Rotation of actuator 71 causes needle 62to advance through body portion 70 to extend tip 68 of the needle intothe tissue mass, as illustrated in FIG. 2B. As illustrated in FIG. 7B,this causes the tissue to become tented over grooves 81. The clinicianthen slowly depresses piston 74 of syringe 64 to cause the bioactiveagent to flow through lumen 82 of the needle and exit through apertures81 to fill grooves 81.

After piston 74 has been depressed a desired distance, actuator 71 isrotated in the reverse direction to withdraw tip 68 from the needletrack, thereby leaving the bioactive agent deposited within the needletrack. Piston 74 of syringe 64 either may be gently depressed duringrotation of actuator 71, so that additional bioactive agent is drawnthrough grooves 81 and lumen 82 by capillary action, or alternativelythe piston of the syringe may be moved to a position where no additionalbioactive agent is dispensed within the needle track during withdrawalof the tip 68. Catheter 61 then may be repositioned within the organ andthe process repeated.

Referring now to FIGS. 8A and 8B, an alternative embodiment of a needlesuitable for use in the delivery system of the present invention isdescribed. The proximal portion of needle 90 is similar in constructionto needle 62 of FIGS. 6, and is coupled at its proximal end to a handle,such as shown in FIGS. 6, that enables needle 90 to be extended into atissue mass. Needle 90 comprises 91 through which bioactive agent may bedispensed from a syringe coupled to the handle, and further compriseslumen 92 that extends the full length of the needle.

Wire 93 is slidably disposed in lumen 92 with its proximal end coupledto an actuator button on the handle and distal end 94 extending acrossand affixed to portion 95 of tip 96 of the needle. Wire 93 is arrangedso that it may be selectively translated distally through lumen 92 byactuating the button on the handle. When extended, wire 93 bows awayfrom the tip 96, and creates pocket P′ in tissue T′ adjacent to tip 96.Wire 93 therefore functions in a manner similar to grooves 81 of theembodiment of FIGS. 7, and enables the bioactive agent to be depositedinto the needle track with little or no mechanical stress or barotrauma.

Operation of needle 90 is similar to that described hereinabove for theembodiment of FIGS. 7, except that wire 93 is deployed prior todeposition of the bioactive agent. In addition, wire 93 preferably iscollapsed to its contracted state before withdrawal of needle 90 fromthe needle track.

Turning to FIGS. 9A-9C, a more detailed description of guide members 32and 65 of the delivery system of the present invention is presented. Asdiscussed hereinabove with respect to catheter 31 of the delivery systemof FIGS. 4 and catheter 61 of the delivery system of FIGS. 6, guidemembers 32 and 65, respectively, are provided for guiding positioning ofthe needle during insertion into a hollow body organ, such as the leftventricle of the heart. The use of guide systems has been proposed inthe art for transmyocardial revascularization systems, and such guidesystems may be advantageously employed in the context of the presentinvention.

FIGS. 9A and 9B are side and end views, respectively, of a guide memberand guide system suitable for use with the delivery system of thepresent invention. Guide system 100 illustratively includes guide member101 disposed on a distal region of catheter 102, wherein the cathetercarries two selectively extendable and retractable needles 103 and 104such as described hereinbove. Guide member 101 comprises a U-shapedchannel that may be engaged to freely translate along preformed rail 105a.

As illustrated in FIG. 9C, four rails 105 a, 105 b, 105 c and 105 d maybe joined at their distal ends to form cage 106 that may be expandedwithin a hollow-body organ to position the distal tip of catheter 102 ata selected position adjacent to the interior surface of the organ. Cage106 may be advanced along guide wire 107 having atraumatic J-shaped tip108. Each of rails 105 a-105 d may include one or more radio-opaquemarkers 109, that permit the rails to be distinguished one from theother under fluoroscopic imaging.

An illustrative use of the apparatus of the present invention to delivera bioactive agent, such as stem cells, to an infarcted portion of apatient's heart is now described. First, guide wire 107 is advanced intothe patient's left ventricle via a femoral artery and the descendingaorta. Cage 106, which may be constrained in a contracted deliveryconfiguration within a sheath, then is advanced along guide wire 107until it is disposed within the left ventricle, for example, asconfirmed by fluoroscopy. The sheath is then retracted to permit cage106 to deploy to its expanded state, wherein rails 105 a to 105 d expandoutwardly into contact with the endocardial surface.

Next, guide member 100 of catheter 102 is engaged with a selected one ofrails 105 a-105 d, and advanced along the rail into the left ventricle.Once the position of the distal tip of the catheter is confirmed withinthe left ventricle, the needle may be extended to deposit the bioactiveagent within the myocardium, as described above for the embodiments ofFIGS. 4-6. Once the needle is retracted, the catheter may berepositioned along the same rail, or withdrawn and reinserted along oneof the other rails, to repeat the process of depositing bioactive agentat selected sites with the myocardium. The cage can be recaptured in theretrieval sheath and rotated slightly before being released againallowing homogenous target myocardial treatment. Upon completion of thisprocess, the catheter is removed, and the sheath may be reinserted tocollapse and remove cage 106. Guide wire 107 then may be removed.

Referring now to FIGS. 10A and 10B, a delivery system of the presentinvention that uses an alternative guide system is described. Deliverysystem 110 includes catheter 111, similar in construction to that ofFIGS. 6, and configured to be advanced along guide system 112 similar tothat described in U.S. Pat. No. 5,830,210 to Rudko et al. Catheter 111includes handle 113 at its distal end and includes side port 114 towhich syringe 115 containing a suitable bioactive agent may be coupled.Guide system includes proximal end 116 and plurality of rails 117 at itsdistal end. Sheath 118 is slidable disposed over rails 117 and may beselectively advanced or retracted to transition the rails between adeployed configuration, where the rails expand into contact with theendocardial surface, and a contracted configuration. Rails 117 mayinclude different numbers of radio-opaque markers 119 to distinguish therails form one another under fluoroscopic imaging.

Catheter 111 includes guide member 119 slidably coupled to a selectedone of rails 117, so that the distal end of the catheter may beselectively positioned along the rail. Needle 120, of which only thedistal tip is visible in FIG. 10B, may be selectively extended andretracted to deposit bioactive agent within the myocardium as describedhereinabove with respect to the embodiment of FIGS. 6. Accordingly,guide system 112 permits the delivery system to be positioned as shownin solid line by needle 120 to deliver bioactive agent into themyocardium, and then later repositioned at the positions shown in dottedline at 120′ and 120″.

Once the needle has been deployed along the length of rail 117, it isnot necessary to withdraw and reinsert catheter 111 along a differentone of the rails 117, as in the embodiment of FIGS. 9. Instead, guidesystem 112 may be collapsed slightly from its fully expandedconfiguration, rotated a desired angle about its axis L, and thenre-expanded to bring needle 120 into alignment with a different portionof the endocardial surface. This process may be repeated a desirednumber of times by the clinician, under fluoroscopic guidance, todeposit the bioactive agent in the myocardium with a predeterminedpattern.

With respect to FIGS. 11A to 11C, another alternative configuration of aguide system suitable for use with the delivery system of the presentinvention is described. Delivery system 130 includes catheter 131,similar to that of FIGS. 4-6, and configured to be advanced along guiderail 132 similar to that described in U.S. Pat. No. 5,730,741 toHorzewski et al. Guide member 133 of catheter 131 comprises an internallumen disposed within the interior of the catheter that enables thecatheter to be translated along guide rail 132, although the externalarrangement of the guide member, as shown in FIGS. 4-6, may besubstituted.

Guide rail 132 includes portion 134 that expands to a helicalconfiguration when released from a delivery sheath (not shown). Rail 132preferably includes atraumatic bumper 135 at its distal end that engagesthe left ventricle near the apex. Catheter 131 preferably includes aradio-opaque marker 136 disposed near tip 137 that permits the clinicianto locate the tip of the catheter as it is advanced along guide rail132.

Operation of the delivery system 130 is described with respect to FIG.11B, where guide rail 132 is shown deployed in the left ventricle. Forexample, guide rail may first be inserted, contracted within a sheath,via a femoral artery route into left ventricle LV. The sheath then isremoved so that portion 134 of guide rail 132 expands into a helicalconfiguration that contacts the endocardial surface.

Next, catheter 131 is advanced along the guide rail under fluoroscopicguidance until distal tip 137 of the catheter is located at a desiredposition adjacent to the endocardial surface. Needle 138 then isextended beyond the tip of catheter 131 to deposit bioactive agent Binto the myocardium along the needle track, as described hereinabovewith respect to the embodiments of FIGS. 4-6. Once the bioactive agentis deposited within the myocardium at the selected site, needle 138 isretracted into catheter 131, and the catheter is advanced or retractedalong guide rail 132 to dispose distal tip 137 at a new location. Theprocess is repeated until the bioactive agent B has been deposited at aplurality of sites as illustrated in FIG. 1C. Catheter 131 then isremoved, and guide rail 132 may be re-sheathed to its collapsedconfiguration and removed, completing the procedure.

A further alternative configuration of a guide system suitable for usewith the delivery system of the present invention is described withrespect to FIGS. 12A-12D. Delivery system 140 includes catheter 141,similar to that of FIGS. 4-6, which has a flexible distal region thatmay be configured in-situ by advancing any of a plurality ofinterchangeable stylets, illustratively, stylets 142 a (FIG. 12A), 142 b(FIG. 12B) and 142 c (FIG. 12C) within the device once it is locatedwithin the left ventricle. Guide member 143 of catheter 141 comprisesinternal lumen 144 disposed within the interior of the catheter thatenables the catheter to be initially translated along a conventionalguide wire, although the external arrangement of the guide member, asshown in FIGS. 4-6, also may be substituted. Once disposed in the leftventricle, the guide wire is withdrawn and a selected one of the styletsinserted.

Each stylet 142 a-142 c has a predetermined configuration that assistsin urging catheter 141 against a selected portion of the endocardialsurface. Each of stylets 142 a-142 c preferably includes atraumaticJ-shaped termination 145 at its distal end that engages the leftventricle near the apex. Catheter 141 preferably includes radio-opaquemarker 146 disposed near tip 147 that permits the clinician to locatethe tip of the catheter as it is advanced along the stylet. In addition,each stylet may include spaced-apart radioopague markers, e.g., every 1cm, so that the clinician can radiographically verify the injectionlocations by aligning marker 146 sequentially with the markings on theselected stylet.

Operation of the delivery system 140 is as follows. First, an atraumaticguidewire is placed in the left ventricle. Over this wire catheter 141is advanced to the left ventricular apex. The guidewire is then removedand a stylet (for example 142 a) is advanced into the catheter until itexits near the apex. The stylet will have a predetermined shape thatwill direct the catheter 141 into the target region of myocardium.Ridges in the catheter will also help direct delivery system 148preferentially towards the endocardium. Second, catheter 141 isgradually retracted and multiple treatments are administered in thisregion at predetermined distances apart. Lastly, the catheter 141 isadvanced back over the stylet into the left ventricular apex and stylet142 a is exchanged for another (for example 142 b). The process is thenrepeated. Alternatively a selected stylet, e.g., stylet 142 a, isinserted into the patient's left ventricle LV via a femoral arteryroute. The stylet may be constrained within a retractable sheath (notshown) that then is removed so that the stylet assumes a predeterminedshape that contacts a portion of the endocardial surface.

Next, catheter 141 is advanced along the stylet under fluoroscopicguidance until distal tip 147 of the catheter is located at a desiredposition adjacent to the endocardial surface. Needle 148 then isextended beyond the tip of catheter 141 to deposit bioactive agent Binto the myocardium along the needle track, as described hereinabovewith respect to the embodiments of FIGS. 4-6. Once the bioactive agentis deposited within the myocardium at the selected site, needle 148 isretracted into catheter 141, and the catheter is advanced or retractedalong stylet 142 a to dispose distal tip 147 at a new location. Theprocess is repeated until bioactive agent B has been deposited at aplurality of sites along the length of the stylet.

Catheter 141 is then fully advanced into the left ventricle, whilestylet 142 a is withdrawn from catheter 141, and stylet 142 b, having adifferent preformed shape, is inserted into lumen 144 to urge catheter141 against a different portion of the endocardial surface (FIG. 12B).Needle 148 then is extended to deposit bioactive agent B at locationsalong the length of the stylet. In addition, stylet 142 b may be rotatedthrough a predetermined angle relative to its longitudinal axis toreposition the catheter within the section of endocardial surfacecorresponding to the selected stylet, and additional needle tracksformed.

Stylet 142C then may be exchanged for stylet 142 b, and the aboveprocess repeated to deposit the bioactive agent at additional locationswithin the myocardium. FIG. 12D illustrates the pattern of bioactiveagent B seeded needle tracks that may be formed using delivery catheter141 and stylets 142 a-142 c of the present invention. As will beapparent to one of skill in the art of medical devices, the stylets maybe made in more or fewer predetermined shapes as required for thespecific medical application and organ to be treated.

In addition to delivery of a bioactive agent via the endocardialsurface, the present invention also contemplates delivery of a bioactiveagent via an epicardial route. More specifically, the bioactive agentmay be deposited in the myocardium using the inventive deliverycatheters disposed along an access route via the coronary sinus andcardiac veins. FIG. 13 depicts the cardiac venous system of a typicalhuman heart, which comprises coronary sinus CS that provides drainagefor great cardiac vein GCV, middle cardiac vein MCV, and small cardiacvein SCV. Deoxygenated blood flowing into coronary sinus CS exits viacoronary ostium O into the right atrium.

It is known in the art to access the epicardial surface via a coronaryvein to provide transvenous retrograde myocardial perfusion, asdescribed, for example, in U.S. Pat. No. 5,655,548 to Nelson et al. andto deliver drugs into the myocardium, as described in U.S. Pat. No.6,159,196 to Ruiz. The present invention may advantageously employ thisaccess route with the atraumatic injection techniques implemented by themethods and apparatus of the present invention.

Referring to FIG. 14, delivery system 150 includes catheter 152 havingguide wire lumen 152 and needle lumen 153. Elongated needle 154, such asdescribed above with respect to FIGS. 6 and 7, is translatably disposedin needle lumen 153. The proximal portion of needle 154 may be similarin construction to that of the embodiment of FIGS. 6, and furtherincludes radio-opaque marker 155 that is visible under fluoroscopicimaging. Distal portion 156 of needle 154 may be sufficiently flexibleto bend through the curve imposed by needle lumen 153, so as to extendfrom the lateral surface of the catheter. Guide wire lumen 152 isconfigured to accept conventional guide wire 157, as depicted in FIG.14.

In FIG. 15A, catheter 151 is shown disposed in coronary sinus CS onguide wire 157. This may be accomplished by first placing guide wire 157via a femoral vein. Catheter 151 then is advanced along the guide wireuntil its distal end passes through the right atrium and coronary ostiuminto the coronary sinus. Once positioned in the coronary sinus CS or anadjoining coronary vein, needle 154 is extended from needle lumen intothe myocardium, as depicted in FIG. 15B. Bioactive agent B, such as asuspension of stem cells, then is deposited in the needle track formedby needle 154.

Needle 154 then is retracted, and catheter 151 may be advanced furtheralong guide wire 157 to deposit the bioactive agent along additionalsites in the myocardium accessible via the coronary veins. While use ofthe coronary veins in this manner simplifies the delivery system byobviating the guide systems of FIGS. 6-9, epicardial access via thecoronary veins will be limited to the sites accessible from those veins.

While preferred illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

1. Apparatus for depositing a bioactive agent into a tissue mass of ahollow organ, the apparatus comprising: a catheter having a proximal endand a distal region and a lumen extending therebetween; an elongatedmember disposed within the lumen of the catheter, the elongated memberhaving a proximal end, a tissue-piercing distal end, and a lumenextending therebetween; and an actuator operatively coupled to theelongated member, wherein during a first range of motion the actuatorextends the tissue-piercing distal end of the elongated member into thetissue mass to form a needle track, and wherein during a second range ofmotion the actuator retracts the tissue-piercing distal end of theelongated member from the tissue mass while atraumatically deliveringthe bioactive agent into the needle track via the lumen of the elongatedmember.
 2. The apparatus of claim 1 wherein the elongated memberdelivers the bioactive agent into the needle track using capillaryaction during retraction of the tissue-piercing distal end of theelongated member.
 3. The apparatus of claim 2 further comprising acontainer holding a quantity of the bioactive agent, the containercoupled to the lumen of the elongated member, and a one-way valve thatrelieves negative pressure within the container.
 4. The apparatus ofclaim 3 further comprising a valve that selectively couples thecontainer to the lumen of the elongated member.
 5. The apparatus ofclaim 1 wherein the tissue-piercing distal end of the elongated membercomprises means for creating a space in the tissue mass adjacent to thetissue-piercing distal end to receive the bioactive agent.
 6. Theapparatus of claim 5 wherein the means for creating the space adjacentto the tissue-piercing distal end comprises a portion of thetissue-piercing distal end defining one or more grooves, and one or moreapertures disposed in the one or more grooves that communicate with thelumen of the elongated member.
 7. The apparatus of claim 5 wherein themeans for creating the space adjacent to the tissue-piercing distal endcomprises a wire disposed across the tissue-piercing distal end, thewire having a contracted insertion state and an expanded stateconfigured to form the space in the tissue mass adjacent to thetissue-piercing distal end, the space comprising a pocket.
 8. Theapparatus of claim 1 wherein the actuator comprises a lever thattranslates the elongated member in proximal and distal directions. 9.The apparatus of claim 1 wherein the actuator comprises a threadedportion that is rotated to cause extension and retraction of theelongated member.
 10. The apparatus of claim 1 wherein the catheter hasa distal end, the lumen of the catheter extends between the proximal anddistal ends of the catheter, and wherein during the first range ofmotion the actuator extends the tissue-piercing distal end of theelongated member beyond the distal end of the catheter.
 11. Theapparatus of claim 1 wherein the catheter has a lateral surface in thedistal region, the lumen of the catheter opens to the lateral surface,and wherein during the first range of motion the actuator extends thetissue-piercing distal end of the elongated member beyond the lateralsurface of the catheter.
 12. The apparatus of claim 1, furthercomprising a guide system comprising a guide member and at least onemember configured to urge the catheter against an interior surface ofthe hollow organ, the guide member affixed to the distal region of thecatheter, the guide member slidably engaged with the at least onemember.
 13. The apparatus of claim 12 wherein the guide member comprisesan internal lumen of the catheter and the at least one member comprisesa stylet having a predetermined deployed shape.
 14. The apparatus ofclaim 12 wherein the at least one member comprises a portion thattransitions to a helical configuration in a deployed state.
 15. Theapparatus of claim 12 wherein the guide system further comprises aplurality of rails having a contracted delivery state and a deployedstate, wherein the plurality of rails contact the interior surface ofthe hollow organ.
 16. The apparatus of claim 12 wherein the at least onemember comprises a plurality of rails, the guide member configured to betranslated along any desired one of the plurality of rails. 17.Apparatus for depositing a bioactive agent into a tissue mass of ahollow organ, the apparatus comprising: a catheter having a proximal endand a distal region and a lumen extending therebetween; an elongatedmember disposed within the lumen of the catheter, the elongated memberhaving a proximal end, a tissue-piercing distal end, and a lumenextending therebetween; an actuator operatively coupled to the elongatedmember, wherein during a first range of motion the actuator extends thetissue-piercing distal end of the elongated member into the tissue massto form a needle track, and wherein during a second range of motion theactuator retracts the tissue-piercing distal end of the elongated memberfrom the tissue mass while atraumatically delivering the bioactive agentinto the needle track via the lumen of the elongated member; and meansfor stabilizing the catheter and the elongated member within the holloworgan.
 18. The apparatus of claim 17 wherein the elongated memberdelivers the bioactive agent using capillary action during retraction ofthe tissue-piercing distal end of the elongated member.
 19. Theapparatus of claim 18 further comprising a container holding a quantityof the bioactive agent, the container coupled to the lumen of theelongated member, and a one-way valve that relieves negative pressurewithin the container.
 20. The apparatus of claim 19 further comprising avalve that selectively couples the container to the lumen of theelongated member.
 21. The apparatus of claim 17 wherein thetissue-piercing distal end of the elongated member comprises means forcreating a space in the tissue mass adjacent to the tissue-piercingdistal end to receive the bioactive agent.
 22. The apparatus of claim 21wherein the means for creating the space adjacent to the tissue-piercingdistal end comprises a portion of the tissue-piercing distal enddefining one or more grooves, and one or more apertures disposed in theone or more grooves that communicate with the lumen of the elongatedmember.
 23. The apparatus of claim 21 wherein the means for creating thespace adjacent to the tissue-piercing distal end comprises a wiredisposed across the tissue-piercing distal end, the wire having acontracted insertion state and an expanded state configured to form thespace in the tissue mass adjacent to the tissue-piercing distal end, thespace comprising a pocket.
 24. The apparatus of claim 17 wherein theactuator comprises a lever that translates the elongated member inproximal and distal directions.
 25. The apparatus of claim 17 whereinthe actuator comprises a threaded portion that is rotated to causeextension and retraction of the elongated member.
 26. The apparatus ofclaim 17 wherein the catheter has a distal end, the lumen of thecatheter extends between the proximal and distal ends of the catheter,and wherein during the first range of motion the actuator extends thetissue-piercing distal end of the elongated member beyond the distal endof the catheter.
 27. The apparatus of claim 17, further comprising aguide system comprising a guide member and at least one memberconfigured to urge the catheter against an interior surface of thehollow organ, the guide member affixed to the distal region of thecatheter, the guide member slidably engaged with the at least onemember.
 28. The apparatus of claim 27 wherein the guide member comprisesan internal lumen of the catheter and the at least one member comprisesa stylet having a predetermined deployed shape.
 29. The apparatus ofclaim 27 wherein the at least one member comprises a portion thattransitions to a helical configuration in a deployed state.
 30. Theapparatus of claim 27 wherein the guide system further comprises aplurality of rails having a contracted delivery state and a deployedstate, wherein the plurality of rails contact the interior surface ofthe hollow organ.
 31. The apparatus of claim 27 wherein the at least onemember comprises a plurality of rails, the guide member configured to betranslated along any desired one of the plurality of rails.